Prediagnostic CT or MRI Utilization and Outcomes in Hepatocellular Carcinoma: SEER-Medicare Database Analysis

Ultrasound-based surveillance has suboptimal sensitivity for early hepatocellular carcinoma (HCC) detection, generating interest in alternative surveillance modalities. We aim to investigate the association between prediagnostic CT or MRI and overall survival in a contemporary cohort of patients with HCC. Using the Surveillance Epidemiology and End Results (SEER)-Medicare database, we analyzed Medicare beneficiaries diagnosed with HCC between 2011 and 2015. Proportion of time covered (PTC) was defined as the proportion of the 36-month period prior to HCC diagnosis in which patients had received abdominal imaging (ultrasound, CT, MRI). Cox proportional hazards regression was used to investigate the association between PTC and overall survival. Among 5,098 patients with HCC, 3,293 (65%) patients had abdominal imaging prior to HCC diagnosis, of whom 67% had CT/MRI. Median PTC by any abdominal imaging was 5.6% [interquartile range (IQR): 0%–36%], with few patients having PTC >50%. Compared with no abdominal images, ultrasound [adjusted HR (aHR): 0.87, 95% confidence interval (CI): 0.79–0.95] and CT/MRI group (aHR: 0.68, 95% CI: 0.63–0.74) were associated with improved survival. Lead-time adjusted analysis showed improved survival continued to be observed with CT/MRI (aHR: 0.80, 95% CI: 0.74–0.87) but not ultrasound (aHR: 1.00, 95% CI: 0.91–1.10). Increased PTC was associated with improved survival, with a larger effect size observed with CT/MRI (aHR per 10%: 0.93, 95% CI: 0.91–0.95) than ultrasound (aHR per 10%: 0.96, 95% CI: 0.95–0.98). In conclusion, PTC by abdominal images was associated with improved survival in patients with HCC, with potential greater benefit using CT/MRI. Regular utilization of CT/MRI before cancer diagnosis may have potential survival benefit compared to ultrasound in patients with HCC. Significance: Our population-based study using SEER-Medicare database demonstrated that proportion of time covered by abdominal imaging was associated with improved survival in patients with HCC, with potential greater benefit using CT/MRI. The results suggest that CT/MRI surveillance may have potential survival benefit compared with ultrasound surveillance in high-risk patients for HCC. A larger prospective study should be conducted for external validation.


Introduction
Patients with cirrhosis or chronic hepatitis B virus (HBV) infection have increased risk of hepatocellular carcinoma (HCC; ref. 1). Surveillance allows surveillance in patients with cirrhosis and reserve their use in select patients with a history or high likelihood of inadequate ultrasound (3).
The extent to which CT/MRI are being utilized for HCC surveillance in the United States and their impact on overall survival (OS) in patients with HCC remain unknown. Therefore, we aimed to estimate the utilization of ultrasound, CT/MRI within 3 years prior to HCC diagnosis and investigate its association with OS in a population-based cohort.

Study Population
We conducted a population-based cohort study using the Surveillance Epidemiology and End Results (SEER)-Medicare database. The linked SEER-Medicare database combines demographic, clinical, and survival information for patients with cancer from the SEER program of cancer registries with Medicare claims information on covered health services from the time of Medicare eligibility until death (17,18). The SEER program collects data on incident cancer cases from 18 cancer registries, including state, central, metropolitan, and the Alaska Native registries, which cover 28% of the United States (17,19,20). Medicare is the primary health insurer for approximately 94% of individuals age 65 years and older, and roughly 90% of Medicare beneficiaries are covered by both Part A (inpatient hospitalizations, skilled nursing facility stays, home health visits, and hospice care) and Part B (outpatient visits and physician office visits/services) benefits (21).
We included all Medicare beneficiaries, ages 68 years and older, who have been diagnosed with HCC [International Classification of Diseases (ICD)-Oncology-3 codes, site: C22.0 AND histology: 8170-8175] from 2011 to 2015. We limited the cohort to individuals ages 68 years and older to ensure 3 years of ascertainment for identification of risk factors and surveillance receipt. We excluded: (i) HCC cases ascertained by direct visualization without microscopic confirmation, or death certificate only; (ii) patients with Medicare Part A and B continuous enrollment fewer than 3 years; (iii) patients with less than 6-month follow-up time after HCC diagnosis to ensure complete capture of HCC-directed treatment; and (iv) patients enrolled in Medicare health maintenance organization plans as these plans were not required to submit individual claims information for services to the Centers for Medicare and Medicaid Services.
This study was conducted in accordance with Declaration of Helsinki and was approved by the NCI and a representative of the SEER registries for the use of the SEER-Medicare data.

Study Variables
Variables of interest included sex, age, race/ethnicity [defined as non-Hispanic White, Black, Asian/Pacific Islander (API)/Others, and Hispanic], etiology of HCC, extent of tumor, types of HCC treatment, NCI comorbidity index, the presence of diabetes, cirrhosis, ascites, and hepatic encephalopathy, surveillance for HCC, SEER region stratified by census tract poverty level, metropolitan/nonmetropolitan counties.
We extracted data on abdominal ultrasound and contrast-enhanced crosssectional images (CT, MRI) within 3 years prior to HCC diagnosis, excluding imaging for the same month of HCC diagnosis (22,23). Receipt of abdominal ultrasound (76700 or 76705), contrast-enhanced CT (74160, 74170, or 74177), or MRI (74182 or 74183) was identified using the Current Procedural Terminol-ogy codes. Patients who had at least one CT/MRI within 3 years before HCC diagnosis were classified as the CT/MRI group. Patients who had at least one ultrasound, without CT/MRI, within 3 years before HCC diagnosis were classified as the ultrasound group. Patients without any ultrasound, CT, or MRI within 3 years prior to HCC diagnosis were classified as no imaging group. Proportion of time covered (PTC) was defined as the proportion of the 36-month study period in which patients had received abdominal imaging, with each imaging study providing 7 months of coverage (month of imaging + following 6 months; refs. 22,24). For patients receiving imaging within 7 months before HCC diagnosis, the number of months of coverage were calculated from imaging to HCC diagnosis.
To define liver disease etiology, Medicare claims ICD, 9th revision or 10th revision codes were used for hepatitis C virus (HCV), hepatitis B virus (HBV), alcoholic liver disease (ALD), NAFLD, and others. As NAFLD is often undercoded, patients with ICD-9 or 10 code for obesity, diabetes, history of bariatric surgery or both dyslipidemia and hypertension in the absence of HBV, HCV, alcohol abuse, and other known liver disease were also classified as NAFLD (23). For patients with multiple etiologies, etiology was classified with the following hierarchy (HCV > HBV > ALD > others > NAFLD).
Cirrhosis was defined on the basis of ICD-9 or ICD-10 codes from Medicare claims (25). We used diagnosis and procedure codes 1 year before HCC diagnosis to calculate the NCI comorbidity index as a measure of noncancer comorbidity (26). The NCI comorbidity index was calculated after excluding liver conditions and diabetes to avoid collinearity in multivariable models (23).
Tumor characteristics were extracted from the SEER Patient Entitlement and Diagnosis Summary File. As SEER only provides the number of tumor nodules as a binary variable (unifocal vs. multifocal), we defined early-stage HCC as a single tumor, less than or equal to 5 cm in diameter without vascular invasion or extrahepatic metastasis, as we have previously done (23,27).

Statistical Analysis
Baseline demographic and clinical characteristics were summarized by standard descriptive measures (frequency and percentage for categorical variables and mean ± SD for continuous variables). These characteristics were then compared using Pearson χ 2 test for categorical variables and the t test or one-way ANOVA for continuous variables as appropriate.
Patients who had no follow-up period after diagnosis or died during the same calendar month of HCC diagnosis (0 month follow-up) were excluded from the survival analysis (n = 710). Sensitivity analysis was performed after including those 710 patients who were excluded in the survival analysis. Survival probabilities were estimated using the Kaplan-Meier method and compared using the log-rank test. Cox regression was used to investigate the impact of imaging on OS after adjusting for demographic and clinical characteristics. Two separate multivariable models were developed: one with receipt of any imaging, stratified by modality group (CT/MRI, ultrasound, no imaging) and the other with PTC by ultrasound and CT/MRI. Fine-Gray subdistribution hazard model was used to analyze both HCC-specific and non-HCC deaths, regressing the hazard of death while adjusting for demographic and clinical characteristics (28).
Lead-and length-time biases were corrected using the method proposed by Duffy and colleagues (29,30) Lead time is the time between early cancer detection by screening and when cancer otherwise would present symptomatically, which can lead to perceived survival benefit even if the disease course was not

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Cancer Res Commun; 3(5) May 2023 875 changed. Statistical correction for lead-time bias is based on sojourn time (1/λ), the period during which HCC is asymptomatic but screen-detectable. Following the parametric model by Duffy and colleagues, correction for lead-time bias involves estimation of the additional follow-up time due to lead time in the case of screen-detected cancer (29). The expected additional follow-up time, for a patient with screen-detected cancer known to be dead at time t after diagnosis and E(s) for a patient with screen-detected cancer known to be alive at time t after diagnosis. To correct for lead-time bias, E(s) was subtracted from observed survival time of screendetected patients, which were defined as those who received screening within 6 months prior to HCC diagnosis (29). We assumed an exponential distribution for the sojourn time 1/λ with a mean of 6 months for our base-case analysis, based on prior studies (31)(32)(33); however, we also performed sensitivity analyses with the mean sojourn times of 3 and 9 months.
Length-biased time relates to slow-growing tumors, which are less likely to be fatal, also have a longer asymptomatic period, and therefore are more likely to be screen-detected. Length-time bias was adjusted on the basis of the proportion of patients with slow-growing tumors and the relative risk of death from slow-growing tumors versus aggressive tumors following the method proposed by Duffy and colleagues (29). The relative risk of death from screen-detected versus symptomatic tumors, ϕ, was estimated by the observed probability of death from screen-detected, p 1 , and symptomatic tumors, p 2 , and the observed probability of screen-detected tumors, p 3 , by giving plausible values for a proportion of patients with slow-growing tumors, 1 − q, and the relative risk of death from slow-growing tumors versus aggressive tumors, θ, that is:φ = . We assumed that 20% of HCCs are slow-growing for our base-case analysis (34,35), and we performed sensitivity analyses with proportions of 10% and 30%. For this range of values, plausible values for the relative risk of death from slow-growing tumors versus aggressive tumors were 0.8 and 0.9. We used 0.9 as our base case, and 0.8 as a sensitivity analysis. Thus, in total, we tested six scenarios for length-time bias adjustment.
All statistical analyses were performed using SAS 9.4 (SAS Institute, Inc.) and Stata 16.1 (StataCorp) software with two-sided tests and a significance level of 0.05.

Data Availability
We used the SEER-Medicare Linked Database to generate the data in this study. The SEER-Medicare Linked Database is not publicly available due to the sensitive nature of the data and risk of reidentification. Investigators are required to obtain approval from SEER-Medicare to obtain the data.

Patient Characteristics
Clinical characteristics of the 5,098 eligible patients with HCC are described in Table 1. About two-thirds of patients were male and the mean age was 76.8 years. The cohort was racially diverse with two-thirds non-Hispanic White, 16% API/Others, 13% Hispanic, and 8% non-Hispanic Black. Most patients had low NCI comorbidity scores, with only 10% having high comorbidity. About three-fourths had underlying cirrhosis, and the most common etiologies of liver disease were NAFLD, hepatitis C, and alcohol-associated liver disease.
Only 19% of patients had early-stage HCC, and only 23% of patients underwent curative-intent therapies.

Receipt and Correlates of Abdominal Imaging Prior to HCC Diagnosis
Abdominal imaging was observed in 3,293 (65%) patients within 3 years prior to HCC diagnosis. Of those with imaging, 2,216 (67%) were in CT/MRI group and 1,077 (33%) were in the ultrasound group. Mean time interval between first imaging (ultrasound or CT/MRI) and HCC diagnosis was 560.5 days (SD: 396.7 days). Among 2,216 patients in CT/MRI group, 658 patients had only CT/MRI during the 3 years prior to HCC diagnosis without any ultrasound. There were 440 patients who had a CT/MRI first and an ultrasound later and 1,040 patients who had ultrasound first and CT/MRI later and 78 patients who had first ultrasound and CT/MRI at the same time. Younger age, female sex, hepatitis C etiology, diabetes, presence of cirrhosis, and presence of hepatic encephalopathy was associated with receipt of CT/MRI (Supplementary Table S1). Higher proportion of patients in the CT/MRI group presented with early-stage HCC and received potentially curative treatment than patients in the ultrasound or no imaging group (Table 1).
The median OS and survival probabilities of patients with HCC after adjustment for lead-and length-time biases are summarized in Fig. 2B and Table 3. One-, 3-, and 5-year survival probabilities of patients in the CT/MRI   Survival estimates for no surveillance group were not changed as adjusting lead-or length-time bias. c 95% confidence intervals are not overlapped between each surveillance type.

Imaging type 1-year survival (%) (95% CI) a 3-year survival (%) (95% CI) a 5-year survival (%) (95% CI) a log-rank test
group were significantly higher than patients in the ultrasound or no imaging groups, regardless of the assumption of sojourn times. After adjusting for lead-time bias, multivariable Cox regression analysis (Supplementary Table S2) showed that patients in the CT/MRI group experienced improved survival compared with no imaging group (aHR: 0.80, 95% CI: 0.74-0.87); however, the survival benefit in the ultrasound group was no longer observed (aHR: 1.00, 95% CI: 0.91-1.10). CT/MRI group experienced improved survival compared with ultrasound group after adjusting for the same covariates in Supplementary  Table S2 and lead-time bias (aHR: 0.80, 95% CI: 0.74-0.88).

Discussion
In this large population-based cohort study of U.S. Medicare beneficiaries, we found abdominal imaging was underutilized within 3 years prior to HCC diagnosis. Only 1 in 10 patients had PTC ≥ 50% using ultrasound and 1 in 20 patients had PTC ≥ 50% using CT/MRI. Notably, CT/MRI imaging was associated with better OS in fully adjusted models, although the survival benefit of ultrasound-based imaging was mitigated after adjusting for lead-and length-time biases.
Overall prognosis of HCC is worse than other solid cancer in part due to lower surveillance implementation and presentation at an advanced stage disease.
HCC surveillance is underutilized in the United States and it is recognized as one of the most critical performance gaps across the HCC care continuum (36). A recent meta-analysis of 29 studies, with a total of 118,799 patients reported a pooled estimate for surveillance use of 24.0% (19). Surveillance estimate in the population-based studies was even lower that only 8.8% of HCCs were detected under surveillance (19). Our PTC analysis showed that ultrasound is still the dominant form of imaging and it is being used more than twice compared with CT/MRI within 3 years prior to HCC diagnosis. Recently, Singal and colleagues summarized a conceptual model for the HCC screening continuum and the reasons for surveillance failure (37). One of the key reasons for the low surveillance in HCC compared with other cancers (e.g., breast or colon cancer) is difficulty with the identification of high-risk populations (38,39). Multiple studies showed that lower surveillance receipt among at-risk individuals is in part due to higher prevalence of unrecognized cirrhosis (26,40). Better recognition of cirrhosis via laboratory and imaging-based algorithms may improve the identification of candidates for surveillance implementation.
Accuracy of ultrasound for early-stage HCC detection is limited. A recent meta-analysis showed that ultrasound has 53% sensitivity for detection of earlystage HCC (6). Serum alpha-fetoprotein (AFP) can augment the accuracy of surveillance test but a combination of AFP and ultrasound still has inadequate performance with a 63% sensitivity for early-stage HCC detection (6). This is far lower than the sensitivity of mammogram (70%-90%) for breast cancer (41) and colonoscopy (>95%) for colon cancer detection (42), highlighting a need to have better surveillance tests. This is particularly important as obesity, metabolic syndrome and alcohol-associated liver diseases, predictors of inadequate ultrasound, have been in rapid increase (43), thus the performance of ultrasound for HCC surveillance will likely further decrease. Surveillance with cross-sectional images, particularly with MRI has been getting more attention recently (10). A single-center prospective surveillance study from Korea of 407 patients with cirrhosis compared the accuracy of ultrasound and liverspecific contrast-enhanced MRI for early-stage HCC detection. Compared with ultrasound, MRI had a higher HCC detection rate (86% vs. 28%, P < 0.001) and lower false-positive findings (3.0% vs. 5.6%; P = 0.004; ref. 11). Subsequent costeffectiveness studies also showed that MRI-based surveillance is cost-effective (15,16). Currently, high cost and long scanning time would be a significant barrier for wider adoption of MRI-based surveillance (44). Recently, abbreviated MRI was studied as an attractive option for HCC surveillance by shortening the scanning time with fewer magnetic resonance sequences. Compared with ultrasound, abbreviated MRI was shown to have higher sensitivity (86% vs. 28%, P < 0.001) at specificity >95% for detection of HCC (45). With a lower cost and high accuracy of MRI-based surveillance, indication and implementation for MRI-based surveillance will likely increase in the near future. It should also be noted that cost-effectiveness of such screening will be highly contingent on the medical system. Implementing a low cost streamlined CT/MRI screening could be more effective in the ultrasound with multipayer systems when it is being mandated by law, similar to mammography for breast cancer, to improve the cost-effectiveness of CT/MRI surveillance.
Surveillance with cross-sectional images will likely improve early HCC detection and a higher likelihood of curative treatment, thus improving OS. However, the potential limitation of CT/MRI surveillance should be carefully considered. For example, it can lead to overdiagnosis of HCC, defined as detecting clinically insignificant, indolent disease that would not impact lifespan expectancy (46). This potential is particularly true for detection and diagnosis of tumors between 1 and 2 cm, for which the positive predictive value of imaging characteristics is lower than that of larger tumors. This could lead to overtreatment, resulting in increased costs, as well as physical side effects, psychologic harms, and poorer quality of life (46). It may increase physical and psychologic harm with indeterminate findings that might lead to repeated intravenous contrast images or percutaneous liver biopsy (47,48). Compare with other cancers with wellestablished screening program, net benefit of HCC surveillance program has not been studied rigorously in HCC, but these should be further investigated as we anticipate increasing diagnosis of HCC with effective HCC surveillance programs.
We acknowledge that our study has several limitations. First, SEER-Medicare lacks granularity, including data on liver disease severity (e.g., model for endstage liver disease, Child-Pugh score) which may affect the indication for HCC surveillance. However, we captured complications of cirrhosis (ascites, hepatic encephalopathy) using ICD-9 or ICD-10 codes. Second, we examined abdominal imaging within 3 years prior to HCC diagnosis as a surrogate for HCC surveillance test, according to our previous publication (22,23), although this operational definition is not concordant with guideline recommendations for semiannual surveillance. We used this definition given the low proportion of patients with any imaging during the study period. To address this limitation, we also measured PTC to consider surveillance as a continuum with various degrees of compliance. Study population in this study is heterogeneous in terms of the way and method of HCC surveillance due to the retrospective nature of the study. However, this reflects the real-life practice of HCC surveillance program in the U.S. general population and the results provide preliminary evidence to conduct prospective randomized controlled trials to address this question. Third, intent of imaging could not be determined in this study given the retrospective nature of the study and many imaging studies were likely performed for nonsurveillance purposes. In the same vein, Current Procedural Terminology codes could not capture more granular clinical data including a specific type of intravenous contrast agent and contrast sequences. Although we have only counted CT/MRI with intravenous contrast, these abdominal images (e.g., CT/MRI for evaluation of abdominal pain using single portal venous phase contrast CT) would not have been optimized for early HCC detection, thus potential survival benefit of CT/MRI surveillance could have been underestimated in the current study.
Finally, Medicare population represents older individuals and the study results might not be generalizable to younger patients with HCC. Despite these limitations, this is the largest contemporary cohort of patients that describes the utilization of CT/MRI prior to the diagnosis of HCC and its association with OS.
In conclusion, abdominal imaging is severely underutilized prior to HCC diagnosis among Medicare beneficiaries in the United States. While both ultrasound and CT/MRI group were associated with better survival compared with no imaging, the results suggest that CT/MRI surveillance may have potential survival benefit compared with ultrasound surveillance. Given the increasing burden of a high-risk population with obesity and metabolic liver diseases, the accuracy of ultrasound as a surveillance test will likely decline.
Therefore, the role of CT/MRI surveillance, its cost-effectiveness, and harms relative to ultrasound should be further investigated in a randomized controlled trial.